The present invention relates to a method for the racemate resolution of both cis- and trans-pyrrolopiperidine, in which a mixture of acyl derivatives of the cis- or trans-pyrrolopiperidine is prepared in the presence of enzymes, and this mixture, following treatment with acids and base, is separated off and by extraction.
Enantiomerically pure pyrrolopiperidines are important intermediates for the preparation of quinolone and naphthyridine derivatives having antibacterial effectiveness (see EP-A 550 903). This EP-A also describes a process for the preparation of enantiomerically pure cis-pyrrolopiperidines in which the racemate resolution is carried out by means of crystallization on 6-benzyl derivatives of the pyrrolopiperidine. A disadvantage in this connection is the complex crystallization of the enantiomers with enantiomeric auxiliary reagents, the two enantiomers each being crystallized using one ancillary reagent.
In a known process for the preparation of other enantiomerically pure secondary amines, hydrolases are used and the acylation must be carried on using esters in which, in the acid moiety, an electron-rich heteroatom (e.g. fluorine) is present in the vicinity of the carbonyl function (see DE-A 43 32 738). Fluoroacetic acid and its esters are more difficult to obtain than unsubstituted aliphatic carboxylic acids and esters thereof.
In a known process for the racemate resolution of primary arnines, the latter are treated with lipase from Candida antarctica and ethyl acetate, with selective acylation of the (R)-isomer (Chimia 48, 570 (1994)). However, this process is limited to the racemate resolution of primary amines.
We have now found a method for the racemate resolution of cis- and trans-pyrrolopiperidine, which is characterized in that a mixture, which comprises (R,R)- and (S,S)-pyrrolopiperidine or (S,R)- and (R,S)-pyrrolopiperidine, is enzymatically monoacylated to give a mixture (I) which comprises (R,R)- and (S,S)-6-acyl-pyrrolopiperidine or (S,R)- and (R,S)-6-acyl-pyrrolopiperidine, this mixture (I) is enzymatically further acylated to give a mixture (II) which comprises (S,S)-1,6-diacyl- and (R,R)-6-acyl-pyrrolipiperidine or (S,R)-1,6-diacyl- and (R,S)-6-acyl-pyrrolopiperidine, the enzyme and optionally solvent and excess acylating agent are separated off from the mixture (II), and the remainder is treated with aqueous acid, and (S,S)-1,6-diacyl-pyrrolopiperidine or (S,R)-1,6-diacyl-pyrrolopiperidine is separated off by extraction, and the extraction residue is rendered alkaline, and (R,R)-6-acyl-pyrrolopiperidine or (R,S)-6-acyl-pyrrolopiperidine is separated off by extraction.